Mizushima et al.

Annals of General Psychiatry 2012, 11:19

http://www.annals-general-psychiatry.com/content/11/1/19

CASE REPORT Open Access

Successful treatment of dopamine dysregulation

syndrome with dopamine D2 partial agonist
antipsychotic drug
Jin Mizushima1,4, Keisuke Takahata1,2, Noriko Kawashima3 and Motoichiro Kato1,4*

Abstract
Dopamine dysregulation syndrome (DDS) consists of a series of complications such as compulsive use of
dopaminergic medications, aggressive or hypomanic behaviors during excessive use, and withdrawal states
characterized by dysphoria and anxiety, caused by long-term dopaminergic treatment in patients with Parkinson’s
disease (PD). Although several ways to manage DDS have been suggested, there has been no established treatment
that can manage DDS without deterioration of motor symptoms. In this article, we present a case of PD in whom
the administration of the dopamine D2 partial agonistic antipsychotic drug aripiprazole improved DDS symptoms
such as craving and compulsive behavior without worsening of motor symptoms. Considering the profile of this
drug as a partial agonist at D2 receptors, it is possible that it exerts its therapeutic effect on DDS by modulating the
dysfunctional dopamine system.
Keywords: Dopamine dysregulation syndrome (DDS), Aripiprazole, Dopamine D2 partial agonistic antipsychotic
drug, Parkinson's disease, Dopamine replacement therapy (DRT)

Background treatment of DDS in a PD patient with a dopamine D2

In the course of long-term antiparkinson therapy, partial agonistic antipsychotic drug.
patients with Parkinson’s disease (PD) often develop dis-
inhibitory non-motor pathologies such as dopamine dys-
regulation syndrome (DDS) and impulse control Case presentation
disorders (ICD) including pathological gambling, hyper- The patient is a 63-year-old male who was diagnosed with
sexuality and compulsive buying. Occasionally, punding PD at age 48, when he began suffering from shuffling gait
or preoccupied repetitive behavior is also observed with of the right foot. He had no previous history of alcohol or
DDS or ICD. DDS refers to excessive and compulsive drug abuse. He also had no history of smoking. Initially, he
use of dopaminergic medications well beyond the dose had been treated with amantadine and pramipexole. How-
needed to control motor symptoms, and it has been typ- ever, within six years, symptoms had worsened and rigidity
ically recognized as a consequence of dopamine replace- of the whole body set in. Medication was then switched to
ment therapy (DRT). Patients with DDS show aggressive levodopa/benserazide. Hoehn & Yahr Scale at this time
or hypomanic behaviors during episodes of excessive use, was ranked as stage II. In the following years, he repeatedly
as well as withdrawal states characterized by dysphoria complained of lower back pain and anxiety. Several medi-
and anxiety. DDS may improve with reduction of the cations including noritriptyline could not alleviate his pain,
dosage of the dopaminergic agent, but many patients are and only levodopa was beneficial. Nine years after begin-
reluctant to decrease levodopa, showing an enduring ning DRT, the patient started self-medication, using exces-
tendency to relapse [1]. Here, we report the successful sive doses of levodopa — up to 2000 mg a day. At the time
he was referred to our hospital, he demonstrated compul-
* Correspondence: [email protected] sive use of levodopa and a withdrawal state including de-
1
Department of Neuropsychiatry, Keio University School of Medicine, 35 pressive symptoms such as anhedonia, loss of interest and
Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
4
Department of Psychiatry, Komagino Hospital, Tokyo, Japan back pain, with impaired social functioning. These depres-
Full list of author information is available at the end of the article sive symptoms were not accompanied with psychotic
© 2012 Mizushima et al. licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative
Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly cited.
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symptoms. His family also reported punding, an intense and alcohol dependence have shown to be relevant to the
preoccupation with repetitive tasks such as carpentry and development of DDS in PD [4]. In our case, the patient
gardening; he often started to strike nails with a hammer had none of these risk factors except for high doses of
suddenly, continuing all day and into the night. EEG and levodopa, reportedly the most important risk factor for
brain MRI demonstrated no abnormal findings, and verbal DDS. Although the exact mechanism underlying DDS
and performance IQ on WAIS-R were 110 and 98, re- remains unknown, it has been postulated that the addictive
spectively. Based on the development of compulsive use liability of dopaminergic agents is mediated by dysregula-
through levodopa therapy, he was diagnosed with DDS. tion of ventral striatal dopamine neurotransmission and
At first, reduction of levodopa medication was initiated abnormal activities of related neural circuitries that consti-
and the patient tried his best not to take excessive medi- tute the reward systems [5]. Supporting this hypothesis,
cations. However, he could not cease the excessive use of human PET studies using [11 C]-raclopride showed
levodopa. At this point, treatment with aripiprazole at enhanced drug-induced dopamine neurotransmission in
6 mg/day was begun. By eleven months, with the dosage the ventral striatum in PD patients with DDS compared to
of aripiprazole having been raised to 18 mg/day, his crav- those without DDS [5]. Thus, alleviation of hyperdopami-
ing for medications (daily dosages and intake intervals) nergic neurotransmission in the ventral striatum is a po-
had considerably subsided. After one year of aripiprazole tential target in the treatment of DDS.
therapy, the dose of levodopa was reduced to 600 mg/ In the present case, we used aripiprazole for the treat-
day without compulsive use, and no punding behavior ment of DDS. There were three reasons for this clinical
was observed. His lower back pain also showed marked choice. First, aripiprazole has a unique pharmacological
improvement, and his depressive symptoms diminished profile that includes partial agonism at dopamine D2
without worsening of motor symptoms. Adverse reac- receptors; it functions as an antagonist in conditions of
tions related to aripiprazole including insomnia, akathi- high, but as an agonist in conditions of low activity of
sia, restlessness and sedation were not observed. the dopamine D2 system [6].This means that aripiprazole
may exert its therapeutic effect via modulation of the
Discussion dopamine system by acting as antagonist during high
Within the past decade, DDS has become recognized as dopaminergic tone and as agonist during the withdrawal
an important complication of dopamine replacement state, and thus the dopamine D2 partial agonistic anti-
therapy, and several medical and surgical options for psychotic drug might represent an effective treatment
DDS have been suggested. One such option is subthala- choice for the compulsive use of levodopa.
mic nucleus deep brain stimulation (DBS), which is The second reason for choosing aripiprazole is its very
accepted as an effective treatment of DDS [2]. However, low risk of adverse effects on motor symptoms of PD [7].
DBS is not without risks, including side effects following It has been reported that even at full receptor occupancy
surgery, impaired cognitive function and psychiatric by aripirazole, extrapyramidal side effects comparable to
complications [3]. Interventions including psychotherapy those expected with other antipsychotics such as haloperi-
and social support are sometimes useful, but these have dol do not occur due to its intrinsic activity on dopamine
only a limited effect in the treatment of DDS. At present, D2 receptors [8]. Also, recent human PET studies of aripi-
the first line of treatment for DDS is generally medica- prazole using [11 C]raclopride and [11 C]FLB457 indicate
tion rationalization. It has been reported that reduction that its intrinsic dopaminergic signal due to its partial
in dopaminergic drug therapies could improve the dis- agonism at dopamine D2 receptors, rather than regional
ability caused by the behavioral disorders associated with distribution of dopamine D2 receptor occupancy, contrib-
DDS. However, dosage reduction of the dopaminergic ute to the minimal risk of extrapyramidal side effects [9].
agent can be troublesome due to worsening of motor Thus, D2 partial agonistic antipsychotic drug displays its
symptoms and neuropsychiatric withdrawal symptoms. therapeutic effects with a minimum possibility of extrapyr-
Furthermore, in the situation where patients may remain amidal side effects. On the other hand, aripiprazole should
sensitized to the dopaminergic agent’s rewarding effects, be used with caution for the treatment of psychosis in PD,
it is often difficult to reduce its dosage. Therefore, a because aripiprazole generally has the adverse effects of
more effective and safe way to manage the addictive li- worsened motor signs and symptoms [10]. However, one
ability of the dopaminergic agent is needed. In this re- previous study suggested that the low doses of aripiprazole
port, we described the therapeutic effect of a dopamine might be tolerable in treatment of PD and display a signifi-
D2 partial agonistic antipsychotic drug on DDS in a pa- cant decrease in the intensity and frequency of L-dopa-
tient with PD. induced dyskinesias [11].
Several risk factors of DDS have been identified. The use Thirdly, several studies have demonstrated the efficacy of
of dopaminergic agents (especially chronic exposure to the dopamine D2 partial agonistic antipsychotic drug
high doses of DRT), a previous history of mood disorders against the compulsive use of alcohol and psychostimulants
Mizushima et al. Annals of General Psychiatry 2012, 11:19 Page 3 of 3
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In our case, aripiprazole successfully improved DDS 12. Bäckström P, Etelälahti TJ, Hyytiä P: Attenuation of reinforcing and
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dopamine D2 partial agonistic antipsychotic drug for DDS
doi:10.1186/1744-859X-11-19
symptoms, and further clinical studies are encouraged. Cite this article as: Mizushima et al.: Successful treatment of dopamine
dysregulation syndrome with dopamine D2 partial agonist antipsychotic
drug. Annals of General Psychiatry 2012 11:19.
Consent
Written informed consent was obtained from the patient
for publication of this case report. A copy of the written
consent is available for review by the Editor-in-Chief of
this journal. This study was done as part of standard care.

Competing interests
The authors declare that they have no competing interests.

Author details
1
Department of Neuropsychiatry, Keio University School of Medicine, 35
Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. 2Molecular Neuroimaging
Program, Molecular Imaging Center, National Institute of Radiological
Sciences, Chiba, Japan. 3Kawashima Neurology Clinic, Kanagawa, Japan.
4
Department of Psychiatry, Komagino Hospital, Tokyo, Japan.

Authors’ contributions
All authors contributed equally during the clinical evaluation and follow-up
period. JM wrote the first draft of the manuscript, and all authors contributed Submit your next manuscript to BioMed Central
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Received: 24 May 2012 Accepted: 7 July 2012
Published: 7 July 2012 • Convenient online submission
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